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Methimazole as an antioxidant and immunomodulator in thyroid cells: mechanisms involving interferon-gamma signaling and H(2)O(2) scavenging
- Source :
- Molecular pharmacology. 60(5)
- Publication Year :
- 2001
-
Abstract
- The antithyroid drug, methimazole (MMI) is used to treat patients with Graves' hyperthyroidism. The major action of MMI is to inhibit synthesis of thyroid hormone in the thyroid gland. However, MMI also has antioxidant and immunomodulatory effects on thyrocytes and/or immune cells. This study identifies novel antioxidant and immunomodulatory effects of MMI involving the interferon-gamma (IFN-gamma) signaling pathway in thyroid cells. MMI inhibits transcription of the intercellular adhesion molecule-1 (ICAM-1) gene by modulating the function of transcription factor STAT1 (signal transducer and activator of transcription 1), which binds to the IFN-gamma activated site of the ICAM-1 promoter. Furthermore, MMI rapidly eliminates H(2)O(2) produced by IFN-gamma treatment in thyroid cells and thus inhibits the H(2)O(2)-mediated phosphorylation of tyrosine 701 in STAT1. MMI also eliminates H(2)O(2) in vitro. MMI facilitates electron transfer from NADPH to H(2)O(2) using thioredoxin or glutathione, fulfilling a role similar to peroxiredoxin or glutathione peroxidase, respectively. MMI prevents the IFN-gamma and H(2)O(2)-mediated reversible inactivation of phosphatases. These effects inhibit full activation of the IFN-gamma-induced Janus kinase(JAK)/STAT signaling pathway in FRTL-5 thyroid cells. These results may in part explain the antioxidant and immunomodulatory effects of MMI in thyroid cells of Graves' disease patients.
- Subjects :
- endocrine system diseases
Thyroid Gland
Gene Expression
Suppressor of Cytokine Signaling Proteins
Antioxidants
Drug Interactions
STAT1
Phosphorylation
Cells, Cultured
Janus kinase 2
Janus kinase 1
Thyroid
Protein-Tyrosine Kinases
Intercellular Adhesion Molecule-1
Protein Inhibitors of Activated STAT
DNA-Binding Proteins
medicine.anatomical_structure
STAT1 Transcription Factor
Peroxidases
Molecular Medicine
Signal Transduction
STAT3 Transcription Factor
endocrine system
Biology
Electron Transport
Interferon-gamma
Suppressor of Cytokine Signaling 1 Protein
Adjuvants, Immunologic
Proto-Oncogene Proteins
medicine
Animals
Pharmacology
Methimazole
Proteins
Hydrogen Peroxide
Janus Kinase 1
Peroxiredoxins
Janus Kinase 2
Rats
Repressor Proteins
Kinetics
Suppressor of Cytokine Signaling 3 Protein
Protein Biosynthesis
STAT protein
Cancer research
biology.protein
Trans-Activators
Tyrosine
Peroxiredoxin
Janus kinase
Carrier Proteins
Hormone
Transcription Factors
Subjects
Details
- ISSN :
- 0026895X
- Volume :
- 60
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Molecular pharmacology
- Accession number :
- edsair.doi.dedup.....f6411a12a5ac60f5f7491b16fca8cbc7